A causal modelling framework for reference-based imputation and tipping point analysis

Abstract: We consider estimating the "de facto" or effectiveness estimand in a randomised placebo-controlled or standard-of-care-controlled drug trial with quantitative outcome, where participants who discontinue an investigational treatment are not followed up thereafter. Carpenter et al (2013) proposed reference-based imputation methods which use a reference arm to inform the distribution of post-discontinuation outcomes and hence to inform an imputation model. However, the reference-based imputation methods were not formally justified. We present a causal model which makes an explicit assumption in a potential outcomes framework about the maintained causal effect of treatment after discontinuation. We show that the "jump to reference", "copy reference" and "copy increments in reference" reference-based imputation methods, with the control arm as the reference arm, are special cases of the causal model with specific assumptions about the causal treatment effect. Results from simulation studies are presented. We also show that the causal model provides a flexible and transparent framework for a tipping point sensitivity analysis in which we vary the assumptions made about the causal effect of discontinued treatment. We illustrate the approach with data from two longitudinal clinical trials.